Our prior work established the foundation for discovering novel insights into the genetic susceptibility and severity of ankylosing spondylitis (AS) as well as genetic-associated mechanistic pathways driving outcomes in this disease. During the renewal of Project 2, we will: 1) expand those insights by combining with another North American cohort of similar size (from Toronto and Edmonton, Canada) that we have already genotyped and followed with almost identical measures (Aim 1); 2) assess and improve cun-ent radiographic scoring systems and determine the characteristics of radiographic progression (Aim 2); and 3) examine a critical association between cardiovascular outcomes and premature mortality in AS while concurrently exploring a relationship between chronic gut inflammation, cardiac morbidity, and AS outcome and mortality (Aim 3). The rationale for Aim 1 comes from the need to examine a robust spectrum of disease phenotype from the very early years of AS through later stage disease. This combined cohort is critical to the analyses of radiographic progression, cardiovascular risk, and gut inflammation addressed in Aims 2 and 3. The rationale for Aim 2 is that the most widely used radiographic scoring system - the modified Stokes Ankylosing Spondylitis Spinal Score (mSASSS), a scoring system that includes measures of erosions, sclerosis, squaring, syndesmophytes, and ankylosis - has several theoretical and methodological limitations for measuring bone formation and disease progression. The rationale for Aim 3 comes from emerging data that the frequency of HLA-B27 in adults from 20-69 years of age declines with increasing age and that unchecked inflammation, presumably from gut ongin, may be responsible for the premature cardiovascular morbidity and mortality that occurs in AS patients relative to the general population. The ability to address these issues during the renewal of Project 2 will allow us to significantly contribute to the understanding of disease initiation, progression, and outcomes in AS.